A study of body composition and its association with disease severity in stable chronic obstructive
pulmonary disease patients in HUSM
By
Dr. Mohammad Faisal bin Asmee
PUM 0065/07
Dissertation submitted in partial fulfilment of the requirement for the Degree of Master of Medicine
Universiti Sains Malaysia ( Internal Medicine )
November 2011
ii
Acknowledgement
Praise to Allah s.w.t the most compassionate and most merciful, whose
blessing have helped me through the entire completion of this dissertation. I wish to
express my utmost gratitude to my supervisor Dr. Shaharudin Abdullah, Dr. Hamid
Jan and Dr. Rosediani who had helped me a lot with their suggestion, interest and
sharing the ideas and encouragement. Without their contribution this thesis would
have been incomplete.
My gratitude also goes to Dr. Kamarul Imran for helping in the statistical
analysis and toward stuff nurse and technician in respiratory clinic for helping in
completing the data collection.
I am most grateful to my parents, wife and children’s for their love, support and
understanding which provided me the inspiration to work hard. Thank you very much
and great appreciation to make this dissertation come true, may Allah blesses us all.
Mohammad Faisal B. Asmee
November 2011
iii
Table of contents Pages
Acknowledgement ii
Table of contents iii
List of tables vi
List of figures vii
List of abbreviations viii
Abstrak (Versi Bahasa Melayu) ix
Abstract ( English version) x
Chapter 1
1.0 Introduction 2
Chapter 2
2.0 Literature review
2.1Definition 5
2.2 GOLD Guideline 5
2.3 Prevalance and burden of COPD 6
2.4 Airflow limitations in COPD 7
2.5 Risk factor for developing COPD 7
2.6 Diagnosing and assessing COPD severity 9
2.7 Systemic effect of COPD 17
2.8 Measurement of nutrition in COPD 21
Chapter 3
3.0 Objectives of the study 24
iv
Chapter 4
4.0 Methodology
4.1 Study Design 26
4.2 Source population 26
4.3 Study approval 26
4.4 Study criteria 27
4.5 Sample size calculation 28
4.6 Sampling method 29
4.7 Data collection 29
4.8 Research equipments 32
4.9 Statistical analysis 34
4.10 Study flow chart 35
Chapter 5
5.0 Results
5.1 Descriptive analysis 37
5.1.1. Demographic data of age, gender and race of study patients 37
5.1.2. Demographic data of smoking among study patients 39
5.2 Clinical variables
5.2.1 Distribution of patients according to GOLD guideline of COPD severity 40
5.2.2 Distribution of all clinical variables 41
5.2.3 Distribution of Body Mass Index 42
5.2.4 Distribution of Fat Free Mass Index 44
5.2.5 Distribution of patients according to usage of steroid inhaler according to
COPD severity 45
5.2.6 Distributions of 6MWD test according to COPD severity 46
5.2.7 Distributions of C-reactive protein 48
5.3 Univariate analysis 49
v
Chapter 6
6.0 Discussion
6.1 Demographic data 56
6.2 Research objectives
6.2.1 Result for FEV1 59
6.2.2 Result for BMI and stage of COPD severity 60
6.2.3 Result for FFMI and stage of COPD severity 62
6.2.4 Result for 6MWD and stage of COPD severity 65
6.2.5 Result for CRP value and stage of COPD severity 67
Chapter 7
7.0 Conclusion 70
Chapter 8
8.1 Study limitationS 72
8.2 Recommendations 73
Chapter 9
9.0 References 75
Chapter 10
10.0 Appendices 81
vi
List of tables
Table 1: The Modified Medical Research Council (MMRC) Dyspnoea Scale
Table 2: COPD stage and its symptoms
Table 3: The BODE index score
Table 4: 6MWD sources of variability
Table 5: Demographic data of age, gender and race distribution of study patients
Table 6: Distribution of smoking history among study patients
Table 7: Distributions of all clinical variables
Table 8: Mean value of six minutes walking distance according to COPD severity
Table 9: Univariate analysis on association of age, gender, race, packed years of
smoking and numbers of years of stopping smoking to COPD severity
Table 10: Univariate analysis on association of body composition to COPD severity
Table 11: Univariate analysis of patients on steroid inhaler with severity of COPD
Table 12: Univariate analysis of body composition according to usage of steroid
inhaler
Table 13: Univariate analysis of six minutes walking distance and lower limb fatigue
during the six minutes walking test according to COPD severity
Table 14: Differences between number of patients according to CRP value with
COPD severity
Table 15: Correlation of study variables with Chronic Obstructive Pulmonary disease
severity
vii
List of figures
Figure 1: Age distribution among study patients
Figure 2: Gender distribution among study patients
Figure 3: Patients distribution according to GOLD guideline of COPD severity
Figure 4: Patients distribution according to WHO Body Mass Index category
Figure 5: Distribution of patients according to Body Mass Index category with COPD
severity
Figure 6: Distribution of patients according to Fat Free Mass with COPD severity
Figure 7: Distribution of patients according to usage of steroid inhaler according to
COPD severity
Figure 8: Distribution of lower limb fatigue among study patients according to COPD
severity group
Figure 9: Patients distribution of C-reactive protein test according to COPD severity
viii
List of abbreviations
n number of patients
COPD Chronic Obstructive Airway Disease
BMI Body Mass Index
ffm fat free mass
ffmi Fat Free Mass Index
6mwd six minutes walking distance
DM diabetes mellitus
GERD gastroesophageal reflux disease
Bph benign prostate hypertrophy
Hpt Hypertension
Ihd Ischaemic heart disease
Hb haemoglobin
FEV1 forced expiratory volume in one second
FEV1/FVC forced expiratory volume in second to forced vital capacity ratio
CRP C-reactive protein
HUSM Hospital University Sains Malaysia
DEXA dual energy X-ray absorptiometry
BIA bioelectric impedance analysis
SFA skin fold anthropometry
ix
Abstrak ( Versi bahasa Melayu )
Latar belakang : Penyakit sumbatan paru-paru kronik bukannya hanya
berkaitan dengan paru-paru sahaja tetapi ia mempunyai manifestasi menyeluruh
disebabkan proses keradangan yang menjadi penyebab penyakit ini berlaku. Ukuran
komposisi badan (indeks jisim tubuh dan indeks jisim tubuh bebas lemak) sebagai
manifestasi menyeluruh penyakit ini telah menunjukkan bahawa ia berkait rapat
dengan kadar keterukan dan kematian kepada pesakit.
Objektif utama kajian ini adalah untuk melihat kaitan antara komposisi badan
dengan tahap keterukan pesakit sumbatan paru-paru kronik yang stabil (tidak
mengalami keterukan yang bertambah dalam jangkamasa tiga bulan sebelum
kajian).
Kaedah : Kami mengkaji 38 pesakit paru-paru kronik stabil yang datang ke
klinik paru-paru HUSM dan mengukur indek jisim tubuh, indek jisim tubuh bebas
lemak, ujian berjalan selama enam minit dan ujian darah untuk CRP.
Keputusan : Kajian ini menunjukkan perbezaan ukuran komposisi badan tidak
mempunyai kaitan dengan tahap keterukan penyakit sumbatan paru-paru kronik
yang stabil (p > 0.05).
Kesimpulan : Ukuran komposisi badan tidak boleh digunakan untuk
menilai tahap keterukan pesakit paru-paru kronik yang stabil.
x
Abstract (English version)
Background: COPD is not just a disease of the lungs alone; it has systemic
manifestations due to the underlying pathogenesis of inflammatory reaction.
Systemic manifestations in term of reduction in body composition (Body Mass Index
and Fat Free Mass Index) has been shown to be an independent risk factor for
disease severity and mortality in COPD.
The objective of this study is to determine the association of body composition
with disease severity in stable COPD patients (patients who had no exacerbation in
the past three months).
Methods: We evaluated 38 stable COPD patients attending Respiratory Clinic
in HUSM and calculated their Body Mass Index, Fat Free Mass Index and
determined their six minutes walking distance and serum CRP values.
Results: There was no satisfactory significant difference between body
composition and disease severity in COPD patients noted in this study ( p > 0.05 ).
Conclusion: Body composition (BMI,FFMI) is not suitable for assessment of
disease severity in stable COPD patients.
2
1. Introduction
Chronic Obstructive Pulmonary Disease (COPD) is one of the most common
respiratory disorder that effect many people worldwide besides asthma, common cold
and chest infections. One of the major leading worldwide work in this illness is the
Global Initiative of Chronic Obstructive Lung Disease (GOLD), that is been conducted
by the World Health Organization. They had produced a guideline to define and
further manage COPD. The GOLD guideline had been accepted worldwide including
in Malaysia whereby base on it, Malaysia has produce its own guideline in 2009
under the Malaysian Clinical Practice Guideline by the Ministry of Health. All this is
done to improve and educate health care professional to manage patient
appropriately.
The definition by GOLD guideline updated in 2010 had included that COPD
have significant extra pulmonary manifestations which may contribute to the severity
of the disease. The systemic illnesses for example are nutritional abnormality (Daniel
A King et al., 2008), weight loss and skeletal muscle depletion (M. Jeffery Mador and
Boskanat., 2001), osteoporosis (Lidwien Graat-Verboom et al., 2009), depression
(Wanning Xu et al., 2008) and anaemia (T. Similowski et al., 2006).
The extra pulmonary manifestation of COPD will be the main focus of this
study whereby its association with COPD severity based on the lung fuction test will
be assessed. The extra pulmonary manifestation that will be look into is the body
composition. This is because based on the previous study, body composition had
been shown to be an independent predictor of disease severity and mortality(Jorgen
3
Vestbo et al., 2006). This is the main evaluation that will be observed in this study as
to further confirm the previous finding to our local data in Malaysia.
From this study, hopefully the use of body composition as one of the
assessments in prevention and treatment of COPD will be established. Another
aspect that would be assesses in this study is patient’s functional capacity according
to their severity of COPD. This is important because body composition was noted to
have a significant correlation with exercise capacity in COPD patients (Eleni Ischaki
et al., 2007).
As for the underlying cause of the extra pulmonary manifestation of COPD,
this study will look into the role of C-reactive protein as the inflammatory marker to
predict the COPD severity. Systemic inflammation had been shown to be the
underlying pathogenesis of COPD and few inflammatory markers was observed to be
elevated in COPD including CRP(Abdullah A. eid et al., 2001).
In conclusion, hopefully from this study data, we could determine the
correlation between body composition and disease severity in COPD patients that
might be helpful in managing COPD patient rather than concentrating on their
respiratory symptoms alone. Further pulmonary rehabilitation or nutritional point of
view might be considered to help improving patient’s quality of life and also in
reducing the mortality related to the illness.
5
2. Literature review
2.1 Definition:
In 2006, the Global Initiative of Chronic Obstructive Airway Disease( GOLD )
had produced a guideline for chronic obstructive airway disease ( COPD ) and
defined it as “Preventable and treatable disease with some significant
extrapulmonary effects that may contribute to the severity in individual patients. The
airflow limitations is usually progressive and associated with an abnormal inflamatory
response of the lung to noxious particle”. In the updated version of 2010 this
definition remains unchanged. Worlwide, ciggarete smoking is the most commonly
encountered risk factor for COPD, although in many countries, air pollution resulting
from the burning of wood and other biomass fuels has also been identified as a
COPD risk factor(Nanshan Zhong et al., 2007)
The primary physiological abnormality in COPD is an accelerated decline in
the forced expiratory volume in one second(FEV1). FEV1 is defined as the maximal
air of a person can exhaled in one second and will shows the degree of airway
obstruction. The COPD symptoms starts from asymptomatic phase in which lung
function deteriorates without associated symptoms. The onset of the subsequent
symptomatic phase is variable and usually starts when the FEV1 fall to less than
50%.
2.2 Global Initiative of Chronic Lung Disease (GOLD) guideline :
The GOLD guideline was initiated in 1998 by the World Health Organization to
bring more attention and awareness to COPD, its management and its prevention.
Therefore it can reduced the morbidity and mortality due to chronic obstructive airway
6
disease. The first GOLD guideline was published in 2001, and since then continous
work were been done to update the guideline yearly by the corresponding commity.
This is because eventhough COPD is considered a major public health problem, its
awareness among the public are still low as compared to other non communicable
disease such as diabetes mellitus, hypertension or ischaemic heart disease (Barbara
P Yawn and Wollan., 2008). The nihilistic attidude among some health care providers
towards managing COPD are still present due to the dissapointment in improving
patient symptoms despite the treatment given ( GOLD guideline updated version
2010 ).
2.3 Prevalance and burden of COPD :
The prevalance of COPD varies in between countries. In year 2006 a meta-
analysis of 37 studies showed that the pooled prevalance was estimated at 7.6% of
the general population(R.J. Halbert et al., 2006) worlwide. In Malaysia, based on the
regional working group 2009, the prevalance of moderate to severe COPD patients
age 30 years or above is estimated at 4.55%. The Global burden of disease study
has estimated that by the year 2020, COPD would be ranked as the third leading
cause of death just after ischaemic heat disease and cerebrovascular accident
(Christopher J L Murray and Lopez, 1997). This had made it moving three steps
further as it is just ranked at number 6th in year 1990. The prevalance and burden of
COPD are projected to increase in the coming decades due to continued exposure to
COPD risk factor and the changing age structure of the world’s population. In 2007
alone, according to World Health Organization, 210 million people have COPD
worlwide with 80 million of them experiencing moderate to severe chronic disease
(Mathers C).
7
Its going to be challenging as this disease is related to lifestyle especially
smoking as the incidence of smoking is increasing and as also as increasing age of
the population(Chen JC and DM., 1999). It would be a burden to patient as it would
be a condition of chronic disability and a burden to the country to manage COPD.
Approximately in year 2000, 2.7 million deaths occurred due to COPD and more than
half of it ocurrs in the Asia-Pasific region including Malaysia(A.d. Lopez et al., 2006).
2.4 Airflow limitations in COPD
The airflow limitations in COPD is due to a mixture of small airway disease (
chronic bronchitis ) and lung parenchymal destruction( emphysema ). It is associated
with abnormal inflammatory reactions towards noxius particles or gases. The most
common noxious particle is from ciggerates smoking and if the exposures remained it
will progressively worsening (A Sonia Buist et al., 2007). Chronic airway
inflammations causes changes and narrowing of the small airways and this leads to
loss of the alveolar attachments to the small airways. Because of this there is a
decreases in the lung elastic recoil that diminishes the ability of the airways to remain
open during expiration. The airway limitations is measured by using the coventional
lung function test which is the spirometry test (Nilva Regina Gelamo Pelelegrino et
al., 2009).
2.5 Risk factor for developing COPD :
There are multiple risk factor that would contribute to the developement of
COPD including genetics, exposure to noxious particles ( eg : tobacco smokes,
organic and inorganic occupational dust ), lung growth and development, oxidative
stress, gender, age, respiratory infections and socioeconomic status.
8
2.5.1 Tobacco smoke
It is estimated that only 15% of smokers develop COPD (A Løkke et al., 2006),
however 90% of the cases of COPD have smoking as their risk factor. This shows
that there are other factors contributing to the development of COPD. World Health
organization estimates that in high-income countries, 73% of COPD mortality is
related to smoking, while in low and middle income countries the rate is 40% (A.d.
Lopez et al., 2006). Back in 1977, Burrow (Burrow., 1977) has already shown that in
a study of general population, there is a highly significant quantitative relationships
between pack years of smoking and fucntional impairment of the FEV1.
Smoking prevention is the most effective intervention to reduce the risk of
developing COPD and stop its progression. Smoking cessation has been shown that
it would reduced inflammatory markers both in patient with or without having chronic
respiratory symptom(B.W.M. Willemse et al., 2004). Stopping from tobacco smokes
also been shown to result in a sustained 50% reduction in the rate of lung function
decline in patient with COPD(Nicholas R. Anthonisen et al., 2002). In the lung health
study, Anthonisen showed that men who stopped smoking at the beginning of the
study and follow up over the 11 years period had a decline of FEV1 rate of 30.2
ml/year compared to those who continue smoking had an FEV1 declined at rate of
66.1 ml/year. This was also true in women where the reduction was 21.5 ml/years in
those who stopped smoking versus 54.2ml/year in those who continued smoking.
2.5.2 Occupational exposure
According to American thoracic Society statement in 2003 (J.Balmes et al.,
2003) occupational exposure may attributed to COPD in 15% of smokers and 31% of
non smokers. Occupational exposure to dust, gas and fumes may cause chronic
9
bronchitis, chronic emphysema, and irreversible airflow obstruction and studies from
both population based and occupational cohort have shown that occupational
exposure is associated with an increased incidence of COPD irrespective of smoking
(Esther Rodríguez et al., 2008).
2.5.3 Genetics
Genetics susceptibility to developed COPD was instituted by the data that only
a minority of cigarette smokers developed COPD. The effects of smoking to lung
function in monozygotic and dizygotic twins shows that when one monozygotic twin
was susceptible to the effects of cigarette smoke, both twins developed reductions in
lung function, whereas other monozygotic twin pairs appeared to be non susceptible
and, despite similar smoking intensity, maintained normal function(Webster PM et al.,
1979). Studies of families and twins suggest that genetic factors also contribute to the
development of COPD. The only established genetic risk factor for COPD is
homozygosity for the Z allele of the alfa-1 antitrypsin gene(A.J. Sandford et al.,
1997). Polymorphism for the genes including alpha 1-antichymotrypsin, vitamin D-
binding protein, microsomal epoxide hydrolase, cytochrome P450 1A1, Glutathione
S-transferase and immunoglobulin A, have also been associated with the
development of COPD(Miki M and k., 1999).
2.6 Diagnosing and assessing COPD severity
The diagnosis of COPD must be considered in patient who has symptoms of
dyspnoea, chronic cough or sputum production with history of exposure to risk factors
for the disease especially to cigarette smoking. Spirometry test is important for
confirmation of COPD and it provides a useful description of the severity of the
10
airflow obstruction in COPD. Spirometry should be done after an adequate dose of
an inhaled bronchodilator to minimise the variability and exclude asthma(Pellegrino R
et al., 2005). A study in a random population sample (Johannessen A et al., 2006)
found the post bronchodilator FEV1/FVC exceeded 70% in all age groups, supporting
the use of this fixed ratio to diagnosed airway obstruction.
2.6.1 Spirometry test
In staging the severity of COPD the Malaysian COPD guideline 2009 had
followed the GOLD guideline 2006 that it is being classified into four groups
according to the post bronchodilator forced expiratory volume in one second (FEV1):
Stage 1: mild FEV1 >80 % predicted
Stage 2: moderate 50 % < FEV1 < 805 predicted
Stage 3 : severe 30 % < FEV1 < 50% predicted
Stage 4 : very severe FEV1 < 30 % predicted or FEV1 < 50 % predicted
plus chronic respiratory failure.
However the relationship between the degrees of limitation based on the
spirometry alone is not perfect. The degree of dyspnoea and disability should also be
use to asses severity which reflects the overall disease impact (D A Mahler and
Wells., 1988) such as by using the Modified Medical Research Council (MMRC)
dyspnoea scale as suggested in the Malaysian Guideline 2009.
11
Table 1: The Modified Medical Research Council (MMRC) Dyspnoea Scale:
Grade of dyspnoea Description
0 Not troubled by breathless except on strenuous execise
1 Shortness of breath when hurrying on the level or walking
up a slight hill
2 Walks slower than people of the same age on the level
because of breathlessness or has to stop for breath when
walking at own pace on the level
3 Stops for breath after walking about 100 m or after a few
minutes on the level
4 Too breathless to leave the house or breathless when
dressing or undressing
On top of that, base on the Malaysian guideline 2009 for COPD also they added the
symptoms that may be present according to the level of COPD :
Table 2: COPD stage and its symptoms
COPD stage
Symptoms that may be present
1 ( Mild ) Chronic cough and sputum production
may be present. At this stage, the
individual is usually unaware that his or
her lung function is abnormal.
2 ( Moderate ) Dyspnoea typically on exertion, cough
12
and sputum production sometimes also
present. This is the stage at which
patients usually seek medical attention
because of chronic respiratory symptoms
or an exacerbation of COPD.
3 ( Severe ) Greater dyspnoea, reduced exercise
capacity, fatigue, and repeated
exacerbations that almost always have
an impact on the patient’s quality of life
4 ( Very severe ) Respiratory failure may lead to cor
pulmonale with signs which include
elevation of the jugular venous pressure
and pitting ankle oedema. At this stage,
quality of life is markedly impaired and
exacerbations may be life threatening.
A multidimensional grading system, the BODE index (Body mass index,
airflow obstruction, dyspnoea and exercise capacity) have a better survival prediction
in COPD patient than FEV1 alone(Bartolome R.Celli et al., 2004). This is because
COPD is not just a disease confined to the lung, but have systemic effects (Agustı,
2005) that would contributes to the COPD morbidities and mortalities that was not
reflected by the FEV1 alone. The BODE index is a multidimensional 10 point scale in
which higher scores indicate a higher risk of death.
13
Table 3: The BODE index score
Variable Points on BODE index
0 1 2 3
FEV1 ≥65 50-64 36-49 ≤35
6 Minute Walk
test ( meters )
≥350 250-349 150-249 ≤149
MMRC
Dyspnoeic
score
0-1 2 3 4
Body Mass
Index
≥21 ≤21
2.6.2 Six minutes walking test
The functional exercise capacity can be determine using the 6 minutes walking
distance(Nilva Regina Gelamo Pelelegrino et al., 2009). This test is to evaluate
objectively the functional exercise capacity for COPD patient. Subjective questions
can be asked to assess functional capacity for example “How many flights of stairs
can you climb” or “How far can you walk”, however this may overestimates or
underestimates the true functional capacity of a patient. The initial walking test was
developed in early 1960’s (Balke, 1963) by measuring the distance walked during a
defined period of time. Later on, a 12 minutes field performance test was developed
to evaluate the functional disability in chronic bronchitis patient (MC Gavin CR et al.,
1976).
The 6 minutes walking test was developed to accommodate patient with
COPD, where a 12 minutes walking test was too exhausting (Butland RJA et al.,
14
1982). It is easier to administer, better tolerated and more reflective of activities of
daily living than the other test(Solway S et al., 2001). This test measures the distance
a patient can walk on a flat, hard ground in a period of 6 minutes. Optimal reference
from healthy population samples using standardization 6mwd methods is not yet
available. A mean of 630 metres was reported in healthy adults (Damien Stevens et
al., 1999). Other study had found the mean of 580m for men and 500m for
women(Miyamoto S et al., 2000). In COPD patient, the walking distance was found to
be less in patient with more severe stage; a mean of 207±40m in stage 4 COPD as
compared to a mean of 455±37m in stage 1 COPD(Eleni Ischaki et al., 2007).
However in Malaysia the walking distance for the 6 minutes walking test was
somewhat more less than other countries. The mean walking distance is about
308.9±160.6m (Ayiesah Ramli et al., 2008) in a study regarding pulmonary
rehabilitation in stable COPD patients at Hospital Universiti Kebangsaan Malaysia.
While comparing among countries(C. Casanova et al., 2011) the mean distance
among different countries are 446±99m for Spain, 225±40m for Venezuela and
311±121m for United States.
There are a lot factors that make the reference range of the 6mwd to be
underestimated or overestimated. Factors that influence the variability of the test was
stated in the American Thoracic Society Statement for the 6 minutes walking test as
stated below:
Table 4: 6MWD sources of variability
Reducing factor Increasing factor
Shorter height
Older age
Taller height
Male sex
15
Higher body weight
Female sex
A shorter corridor
Pulmonary Disease
Cardiovascular disease
Musculoskeletal disorder
High motivation
Patient who had previously performed the test Just taken medication for the disabling disease Oxygen supplement
2.6.3 Body composition
Body composition refers to the proportion of fat and fat free mass in the body.
Fat mass contains the metabolic inactive energy store while fat free mass contains
the metabolic active organs especially the skeletal muscle. Reduction in this skeletal
muscle will directly cause the reduction in lung function and general functional
activity. People who have higher proportion of fat free mass compared to body fat are
considered healthier as they have less weight related problem.
A large study involving 1218 participants (Charlotte Landbo et al., 1999)
demonstrated COPD mortality was significantly higher in underweight subjects as
defined by a low body mass index. Further analysis of the study shows that BMI and
COPD mortality was significantly higher in patient with FEV1 less than 50%. This
indicates that there is a strong interaction between BMI with COPD severity and its
prognosis.
But we still need to consider that body mass index (BMI) includes both the fat
mass and fat free mass index. Therefore measuring BMI alone could be an incorrect
way to measure the skeletal muscle mass in COPD patient. Fat free mass index
16
(FFMI) in the other hand would reflect better prediction of decline in the skeletal
muscle mass.
Therefore the usage of fat free mass index rather than body mass index could
be a more significant parameter of prognostic value in COPD patient. This is
observed from COPD patient from Copenhagen City Heart Study(Jorgen Vestbo et
al., 2006), where even though they have normal BMI, 26.1% of them had a low fat
free mass index. In term of looking into COPD severity, they observed that patients
with normal BMI in stage 3 and 4 COPD according to the FEV1 value, 50% of them
had a low FFMI. Comparing from stage 1 to stage 4 COPD, the FFMI also shows a
decreasing trend from mean of 17.2kg/m2 to 16.1kg/m2 respectively.
Both of the above study used bioelectric impedance analysis to measure the
body composition. The observation of reduction in body composition related to COPD
prognosis was also found when other method being used. This was shown by using
the measurement of mid thigh muscle area using CT scan(Karine Marquis et al.,
2002). They found that depletion in mid thigh muscle area was a strong predictor of
mortality in COPD patient with FEV1 less than 50%.
2.6.4 C-Reactive Protein
C-reactive protein is an acute phase protein which is found in the blood in
response to inflammation. It is synthesized by the liver in response to factors
released by fat cells. Its physiological role is to bind to phospholipids expressed on
the surface of the dead or dying cells in order to activate the complement system via
the C1Q complexes. In COPD patient it is expected to be elevated as the
pathogenesis of COPD includes inflammatory reaction. As it is an acute phase
17
reactant, CRP will be elevated in patients who have exacerbation of COPD or
infection, therefore patient in this study only includes those who are stable whereby
they were not having any acute exacerbation for the past three months prior to study
date as the inclusion criteria.
Recent advances are looking at local and systemic biomarkers in correlation
with the lung function assessment. CRP in advance COPD were raised in 48 among
102 patients and in these patients their resting energy expenditure were higher and
the six minutes walking test were lower(R. Broekhuizen et al., 2006).
This is supported by other studies that shows not only CRP but Interleukin 6,
fibrinogen and tumour necrosis factor (Jorgen Vestbo et al., 2006) are elevated in
even at a mild stage of COPD and it correlates well with low fat free mass index
which is an independent predictor of mortality despite the lung function test value.
Mainly the studies in CRP level were looking at the highly sensitive CRP level.
When comparing the level between stable COPD patient and control, it was noted to
be significantly higher ( 4.1 mg/l versus 1.8mg/l, respectively p < 0.001) (J.P. de
Torres et al., 2006). Other than that it was also shown that the distance of walking
was significantly reduced in patient with higher CRP level.
2.7 Systemic effect of COPD
COPD as defined before is not a disease only confined to the lung but also
have systemic effects that complicate the disease. This systemic illnesses leads to a
pronounced deterioration in health status and diminished quality of life (R.Shoup et
al., 1997). Although the underlying mechanism of these systemic effects are unclear,
there is growing evidence that it involves systemic inflammation, tissue hypoxia,
18
oxidative stress and inactivity due to skeletal muscle dysfunction(Abdullah A. eid et
al., 2001).
The extra pulmonary condition or the co-morbid illness that are associated
with COPD are; cachexia and malnutrition (Daniel A King et al., 2008); normochromic
normocytic anaemia (T. Similowski et al., 2006); skeletal muscle wasting and
peripheral muscle dysfunction (Noritoshi Nagaya et al., 2005); ischemic heart
disease(José Luis Izquierdo et al., 2010), osteopenia, osteoporosis and bone
fractures (Lidwien Graat-Verboom et al., 2009); sleep disorders, anxiety and
depression (Wanning Xu et al., 2008). The relationships between these pulmonary
and non pulmonary co morbidities are not fully understood, and this further
complicates the assessment of disease severity and prognosis.
2.7.1 Nutritional abnormalities and weight loss
The observation of nutritional abnormalities in COPD had well been
established for many years. Among the earliest evidence of a relationship between
body weight and COPD emerged from a study investigating metabolic imbalances in
severe bronchial obstruction (Vandenbergh E et al., 1967). Nutritional abnormalities
includes alterations in caloric intake, basal metabolic rate, intermediate metabolism
and body composition(Schols, 2000).
There are a growing interest in this parameter as it had been proven that
nutritional abnormalities reflected by the body mass index and fat free mass index to
be an independent predictor of mortality (Jorgen Vestbo et al., 2006), functional
capacity and also in expressing disease severity (Eleni Ischaki et al., 2007). The
study by Jorgen Vestbo in 2006, found that patient who is in the lowest 10th
19
percentile of the general populations for fat free mass index have a higher risk of
COPD related mortality.
The study by Eleni Ischaki in 2007 showed that there were a significant
relationship between FFMI and the 6 minutes walking distance (P< 0.0001). This
significance however was poorly observed if BMI was used to see the correlation with
the 6 minutes walking distance (P>0.01). Therefore body composition measurement
is an important abnormality that would be use for screening and preventive measure
in COPD patient.
Unexplained weight loss occurs in about 50% of patients with severe COPD
and chronic respiratory failure, but it can also be seen in about 10-15 % of patients
with mild to moderate disease (Creutzberg., 1998). Loss of skeletal muscle mass is
the main cause of weight loss in COPD while loss of fat mass contributes to a lesser
extent. The pathophysiological cause of weight loss is most likely attributed to a high
metabolic rate that is not compensated by a corresponding increase in caloric
intake(Creutzberg., 1998).
Because of the close relation between nutritional abnormalities and prognosis
of COPD, further study was done to correct the nutritional aspect of patient. A meta-
analysis (Ivone Martins Ferreira et al., 1998) looking at 272 references, found that
nutritional support by giving caloric supplement for at least 2 weeks, had no effect on
improving anthropometric measures, pulmonary function, respiratory muscle strength
and functional exercise capacity in stable COPD patients. Further study in 2002,
contradict this meta-analysis, whereby oxandrolone ( an anabolic steroid ) had been
shown that it can restore lean body mass in COPD patient after four months of
clinical trial(Shing-Shing Yeh et al., 2002).
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2.7.2 Skeletal muscle dysfunction
Muscle mass dysfunction is an important feature of COPD despite the
spirometry value. It has significant contribution to patient symptoms and prognosis.
The presence of muscle dysfunction was first recognised in a study demonstrating
that many patients with COPD have limited exercise capacity owing to skeletal
muscle dysfunction(Killian., 1992).
The pathogenesis of skeletal muscle dysfunction in COPD patient is probably
due to inactivity, tissue hypoxia and systemic inflammation. Cytokines such as
tumour necrotic factor alpha and oxidative stress can contribute to the protein
inactivation and degradation, resulting in dysfunction, atrophy and apoptosis (Alvar
G. N. Agustí et al., 2002). Other than that, the treatment for COPD itself by giving
steroids can leads to muscle dysfunction by causing skeletal muscle
myopathy(Decramer., 1994).
Although research in attributing the cause of the muscle dysfunction is still
going on, we do know now that it has important consequences including exercise
limitation, reduced quality of life and reduced survival. Therefore as skeletal muscle
depletion is potentially treatable, compared to the pulmonary component; it has a
major role as a target in treating COPD patient. The benefit of this approach is mostly
by using pulmonary rehabilitation as it improves symptoms and reduced disability
(Linda Nici et al., 2006). This would further improve patient quality of life. The
mechanism towards pulmonary rehabilitation is largely due to skeletal muscle
adaptation to physical training (Maltais., 1996).
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2.8 Measurement of nutrition in COPD
Nutritional measurement is based on the body composition which includes the
body mass index and the fat free mass index. The term malnutrition and cachexia are
often used interchangeably and define as body mass index. In assessing nutritional
state for COPD patient, the simple measurement of weight adjusted for height which
is the body mass index may not characterized the overall nutritional state because in
COPD patient the cachexia is more related to the loss of muscle mass which
correlate better to the prognosis even when they have a normal BMI (Annemie M.W.J
Schols et al., 2005).
Schols and co-workers distinguished three different types of impaired nutrition:
semi starvation ( low BMI with normal or above normal fat free mass index ), muscle
atrophy ( low fat free mass index and normal or above normal BMI ) and cachexia (
low BMI and low fat free mass index ). They found that patients in the semi starvation
group had better survival compared to the other two groups indicating that a lower fat
free mass index better predicts the mortality. They also found out that patients with
GOLD stage IV had the highest prevalence of cachexia compared to others.
There is no gold standard method for the measurement of fat free mass index.
The choice of measurement method for body composition includes dual energy X-ray
absorptiometry ( DEXA ), bioelectric impedance analysis ( BIA ) and skin fold
anthropometry ( SFA ). DEXA has been suggested as a suitable clinical reference
method for the measurement of body composition (Van Loan and PR., 1992).
However because of its cost and inconvenience to patient, the bedside evaluation by
using SFA and BIA is the preferred choice.
Compared to DEXA, the sensitivity for detecting nutritional depletion was 86%
for BIA and 74% for SFA, while the specificity is 88% for BIA and 98% for SFA (M.C
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Steiner et al., 2002). Therefore BIA causes underestimation of fat free mass index
relative to DEXA, while SFA causes overestimation. BIA estimates the total body
water from measurement of whole body impedance. Fat free mass is calculated from
total body water using a prediction equation derived from comparison with a
reference method.
In defining the level of fat free mass index there are still ongoing study to
define the standard reference range. In a large study involving 5635 young healthy
Caucasians adults (Schutz., 2002), the median fat free mass index were 18.9kg/m2
for males and 15.4 kg/m2 for females. To see the variation among different ethnic at
different countries, further study was also done (Hull., 2011) involving Caucasian,
African American, Hispanic and Asian in 2010 involving 1339 healthy subjects age
from 18 to 110 years. The total body fat, total fat free mass and bone mineral density
was measured using dual energy X-ray absorptiometry. In this cross sectional study
they found that the mean fat free mass index according to the ethnic group for males
is 20.5 for Caucasian, 21.1 for African American, 20.6 for Hispanic and 18.8 for
Asian. While for female subjects it was 16.6 for Caucasian, 17.4 for African
American, 17.9 for Hispanic and 15.0 for Asian. These differences were statistically
significance among the ethnic groups (P< 0.05).
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3.0 Objective of the study :
Primary objective :
To determine the association between body composition with severity of disease in
Chronic Obstructive Pulmonary Disease patients.
Secondary objectives :
1. To determine the association between BMI and severity of disease in COPD
patients.
2. To determine the association between FFMI and severity of disease in COPD
patients.
3. To determine the association between functional activity and severity of
disease in COPD patients.
4. To determine the association between C-reactive protein (CRP) level and
severity of disease in COPD patients.